Abuse liability and reinforcing efficacy of oral tramadol in humans

Drug Alcohol Depend. 2013 Apr 1;129(1-2):116-24. doi: 10.1016/j.drugalcdep.2012.09.018. Epub 2012 Oct 23.


Background: Tramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist.

Methods: Nine healthy, non-dependent prescription opioid abusers (6 male and 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample and 7 self-administration). During each sample session, an oral dose of tramadol (200 and 400 mg), oxycodone (20 and 40 mg), codeine (100 and 200 mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money.

Results: All active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs.

Conclusions: This study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Analgesics, Opioid / pharmacology*
  • Carbon Dioxide / metabolism
  • Codeine
  • Cohort Studies
  • Double-Blind Method
  • Female
  • Flicker Fusion
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Middle Aged
  • Oxycodone
  • Oxygen / blood
  • Psychomotor Performance / drug effects
  • Pupil / drug effects
  • Receptors, Opioid, mu / drug effects
  • Reinforcement, Psychology
  • Self Administration
  • Substance-Related Disorders / psychology*
  • Tramadol / pharmacology*
  • Young Adult


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Carbon Dioxide
  • Tramadol
  • Oxycodone
  • Codeine
  • Oxygen